Cell cycle deregulation and cardiovascular diseases
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Cell cycle deregulation and cardiovascular diseases. Ana Rita Lobo Diogo Matos Inês Matos. Objectives. Cell cycle Interphase Mitosis Control System of the Cell Cycle Cell cycle machinery and Stroke. Cell Cycle.

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Cell cycle deregulation and cardiovascular diseases

Cellcyclederegulationand cardiovascular diseases

Ana Rita Lobo

Diogo Matos

Inês Matos


Objectives
Objectives

  • Cellcycle

    • Interphase

    • Mitosis

  • ControlSystemoftheCellCycle

  • CellcyclemachineryandStroke


Cell cycle
CellCycle

  • The cell cycle is the series of events which take place in the cell and lead to its duplication by means of replication and duplication of its previous contents.


Cell cycle s phases
Cellcycle’sphases

  • The cell cycle is generally divided into two phases:

    • Interphase - the cell spends most of its time performing the functions that make it unique.

    • Mitosis - the cell divides into two daughter cells.


Interphase
Interphase

  • The interphase stage of the cell cycle includes three distinctive parts:

    • G1phase- follows mitosis and is the period in which the cell is synthesizing its structural proteins and enzymes to perform its functions;

    • S phase-the DNA within the nucleus replicates

    • G2phase-the cell prepares for mitosis. Proteins organize themselves to form a series of fibers called the spindle, which is essential to chromosome movement during mitosis


M itotic p hase
MitoticPhase

  • Themitoticphaseistheperiod in thecellcyclewhereoccurs, thenucleousdivision. Themitoticprocessincludes 4 phases:

    • Prophase

    • Metaphase

    • Anaphase

    • Telophase

  • Afterthemitoticphase, thecytokinesisoccurs: microfilaments contract during cleavage and assist the division of the cell into two daughter cells.


Control system of the cell cycle
ControlSystemoftheCellCycle

  • In themajorityofeukaryoticcells, thecontrolsystemsofthecellcycleactivateitsprogression in threepoints.


Control system of the cell cycle1
ControlSystemoftheCellCycle

Elementsinvolved:

  • Cyclins-dependentkinases (CDKs)

  • Cyclins

  • CDK inhibitorproteins (CKIs)

  • Retinoblastoma protein (Rb)

  • CyclicalProteolysis


Cell cycle deregulation and cardiovascular diseases
CDKs

CYCLINS

  • Cyclins are a family of proteins that have no enzymatic activity of their own but activate CDKs by binding to them.

  • Themaincomponentsofthecontrolsystemofthecellcycle are a memberof a kinases’ familyknown as cyclin-dependentkinasesthat can modify various protein substrates involved in cell cycle progression.

Cyclin

Cyclindependtkinase (CDK)


How do cdks control the cell cycle
How Do CDKs Control the Cell Cycle?

  • All cyclins are named according to the stage at which they assemble with CDKs. Common classes of cyclins include G1/S-phase cyclins, S-phase cyclins, and M-phase cyclins.

  • Because cyclin-CDK complexes recognize multiple substrates, they are able to coordinate the multiple events that occur during each phase of the cell cycle.



Inhibitor phosphorilation and ckis cdk inhibitor proteins
InhibitorphosphorilationandCKIs(CDK inhibitorproteins)

  • Theriseandfallofthecyclinlevels are themaineventsthatcontroltheactivityofCDKsduringthecellcycle.

However, othermechanismshelptheactivityofCDKs in specificstagesofthecycle.


Inhibitor phosphorilation and ckis cdk inhibitor proteins1
InhibitorphosphorilationandCKIs(CDK inhibitorproteins)

  • Thephosphorilation in a pairofaminoacidsonthe top ofthekinases’ active site inhibitsthecyclin-cdkcomplex.

  • Cellsusually use CKIs to helpthem in the G1-S regulationactivity in thebeginningofthecellcycle. There are some typesofCKIssuch as P15,P16,P18 and P19.


Retinoblastoma protein rb
Retinoblastoma protein (Rb)

  • Important target of G1 CDKS

  • In mid- to late- G1, Rbisphosphorylatebycyclin D1- cdk4/6 andcyclin E-cdk2 complexes

  • Rb (hyperphosphorylated) is no longerrepressedby E2F

  • E2F bindswith DP

  • Activate genes required for S phaseprogression


Cell cycle s deregulation and cardiovascular diseases
Cellcycle’sderegulationand cardiovascular diseases

  • Hypothesis:

    Onesignalwhichmaycontrolischemic neuronal deathistheinappropriateactivationofcellcycleregulatorsincludingcyclins, cyclindependentkinases (CDK) andendogenouscyclindependentkinasesinhibitors (CDKI).

    Aberrantactivationoftheseelementstriggers neuronal death


Stroke
Stroke

  • Occludedorrupturedofbloodvesselsand in some cases cardiacarrest.

    Neurons in theaffectedbrainregion are privedofoxigenand glucose.

    Ischemic neuronal deathisdeterminedbylocation, severityanddurationofinsult.


Cell cycle machinery and stroke in vitro evidence
CellcyclemachineryandStrokeIn vitro evidence


Cell cycle machinery and stroke in vitro evidence1
CellcyclemachineryandStrokeIn vitro evidence

J. Rasidian, G.O. Iyirhiaro, D.S. Park, Cellcyclemachineryandstroke, BBA – Molecular BasisofDisease (2006), doi: 10.1016 / j.bbadis.2006.11.009


Cell cycle machinery and stroke in vitro evidence2
CellcyclemachineryandStrokeIn vitro evidence

  • Normal conditions:

  • Thelevelsofactivityofkeycellcycle are downregulated;

  • More activityofCKIs;

  • ThelevelsofhypophosphorylatedRbincreasesresulting in greaterE2F sequestration.


Cell cycle machinery and stroke in vitro evidence3
CellcyclemachineryandStroke In vitro evidence

Ischemicinjuryconditions:

  • LoseofCKIs

    example: CDK inhibitor p27 isreportedlossof CKI followingoxygen glucose deprivation (stroke)

  • Increase in Cyclins

    example: cyclin D1 proteinlevelsandactivationof Cdk2 afterstroke

  • Rbisphosphorylatedfollowinghypoxia/reoxygenation

  • Increase in E2F mRNAtranscription

    Activationofthecellcycle


Cell cycle machinery and stroke
CellcyclemachineryandStroke

Thisonlyshowedtheactivationofcellcyclecomponentsand does notadressstheissueofwhetherthissignalisrequired for death


Cell cycle machinery and stroke1
CellcyclemachineryandStroke

J. Rasidian, G.O. Iyirhiaro, D.S. Park, Cellcyclemachineryandstroke, BBA – Molecular BasisofDisease (2006), doi: 10.1016 / j.bbadis.2006.11.009


Cell cycle machinery and stroke2
CellcyclemachineryandStroke

  • Proceeding 1:use drugsthatinactivatethecellcycle, such as CDK inhibitorslikeflavopiridol

  • Conclusion 1: the cortical neuronshavebeenprotected


Cell cycle machinery and stroke3
CellcyclemachineryandStroke

  • Proceeding 2: geneticmanipulationofcomponentsofthecellcycle

  • Conclusion 2: in micewithexpressingkinasedead cdk4 ornull for itsregulatorcyclin (D1) are resistent to hypoxiamediatedischemicdeath


Cell cycle machinery and stroke4
CellcyclemachineryandStroke

  • Proceeding 3: envisionofthecellcyclepathwaywith E2F null

  • Conclusion 3:cortical neuronsderivedfrom E2F nullmice are lesssusceptible to deathbyhypoxia

    Furthermore E2F deficiency improves therecoveryofneuronsfromlossofsynaptictransmission


Cell cycle machinery and stroke5
CellcyclemachineryandStroke

Takentogether, these in vitro evidencestronglyimplicatethereactivationofcellcyclecomponents in ischemic neuronal death.


Cell cycle deregulation and cardiovascular diseases

Cellcycle role inatherosclerosis

Theatheroscleroticplaqueisdue to anoverproliferationofendothelial, smoothmuscle, andinflammatorycellsandmacrophages

Thedivisionofthesecellsisactivatedby a AllograftInflammatory Factor (AIF-1)


Cell cycle deregulation and cardiovascular diseases

Cellcycle role inatherosclerosis

  • AIF-1 isnotpresentin normal arteries, anditisproducedby VSMC whenthey are stimulated.Constitutiveexpression of AIF-1 results in a shorter cell cycle, and aberrant expression of cell cycle proteins.

  • AIF-1 actively participates in the upregulation of VSMC’s proliferation

Thishappensbecause AIF-1, alongsidewithcalmodulin, shortensthe G1 andantecipatesthe S phase


Cell cycle deregulation and cardiovascular diseases

Cellcycle role inatherosclerosis

  • Thisisimportant to copewiththeinflammatory processes. Butifthishappensinordinarysituations, itmay cause a overproductionof VSM cells, obtructing crucial arteriesofthe cardiovascular system.

AtheroscleroticRestenosis


Bibliography
Bibliography

  • Alberts B., Bray D., Lewis J., M. Raff, Roberts K., & Watson J.D. (1994) Molecular Biology of the Cell, 3rd Ed. Garland Publishing, Inc. New York.

Netgraphy

  • http://www.nature.com/scitable/topicpage/cdk-14046166

  • http://atvb.ahajournals.org/content/21/9/1421.short

  • https://sites.google.com/site/kefalikinisi/home/fisiologia-humana-1/celula-e-celulas/ciclo-celular

  • http://scholar.google.pt/scholar?start=10&q=deregulation+in+cell+cycle+and+cardiovascular+diseases&hl=pt-PT&as_sdt=0

Articles

  •  J. Rasidian, G.O. Iyirhiaro, D.S. Park, Cellcyclemachineryandstroke, BBA – Molecular BasisofDisease (2006), doi: 10.1016 / j.bbadis.2006.11.009

  • Michael V. Autieri, Christopher M. Carbone - Overexpression of Allograft Inflammatory Factor-1 Promotes Proliferation of Vascular Smooth Muscle Cells byCellCycleDeregulation(ArteriosclerThrombVasc Biol. 2001;21:1421-1426.)